As used herein, the term "neuraminidase" means any protein that has neuraminidase activity or has an amino acid sequence that is similar to a protein which has neuraminidase activity. The neuraminidase that can be used to practice the present invention can also be inactivated enzyme or part of the enzyme. The term "herpes related disorder" means any disorder that is effected or mediated by a herpes virus infection. The term "herpes virus" means any virus in the herpes family. These include, but are not limited to, herpes simplex types 1 and 2, Epstein-Barr viruses, varicellazoster, cytomegaloviruses, Herpesvirus simiaeand human herpesvirus-6.
Herpes Virus Infections
More than 50 herpes viruses are known to infect over 30 different species. A. J. Nahmias and B. Roizman, New Engl. J. Med. 289, pp. 667-674 (1973). The most clinically significant of these are the two naturally occurring variants of herpes simplex virus (HSV). Man is the sole reservoir of this virus. The herpes simplex virus was first isolated in 1920. B. Lipschutz, Arch. Derm. Syph. (Berl) 136, pp. 428-482 (1921). In 1961, two serotypes were differentiated. Generally, HSV-1 infects non-genital sites while HSV-2 infects genital sites. It is possible, however, to isolate HSV-1 in a genital herpes case. Transmission is direct. Localized ulcers or lesions in the oral cavity, eye, skin or reproductive tract usually develop after infection. Dissemination can cause encephalitis in neonates and the immunosuppressed. The virus can remain latent, presumably for years, until a relapse is triggered by stress, environmental factors, other medications, food additives or food substances (see A. J. Nahmias and B. Roizman, New Engl. J. Med. 13, pp. 667-674 (1973); W. E. Rawls, E. H. Lennette (eds.), Laboratory Diagnosis of Viral Infections, Marcel Dekker, Inc., New York, pp. 313-328 (1985)).
Another pathogen from the herpes virus group is the Epstein-Barr virus. Discovered in the 1960's, it is the principal etiologic agent of infectious mononucleosis and has been associated with Burkitt's lymphoma and nasopharyngeal carcinoma malignancies (see W. Henle and G. Henle, M. A. Epstein and B. G. Achong (eds.), THE EPSTEIN-BARR VIRUS, Springer-Verlag, Berlin, p. 297 (1979)). Infectious mononucleosis is characterized by lymphadenopathy, fever and pharyngitis. As with the HSV variants, the Epstein-Barr virus may establish a latent infection which may be reactivated when the host is immunosuppressed (see E. T. Lennette, E. H. Lennette (eds.), LABORATORY DIAGNOSIS OF VIRAL INFECTIONS, Marcel Dekker, Inc., New York, pp. 257-271 (1985)).
Also a herpes virus, the varicellazoster (VZ) virus is the causative agent of both varicella (chicken pox) and zoster (shingles). Varicella occurs primarily in childhood, whereas the more localized zoster occurs in the elderly and immunocompromised. Zoster is, in fact, due to a reactivation of a latent VZ infection. Patients suffer painful, vesicular skin lesions (see A. Gershon, E. H. Lennette (eds.), LABORATORY DIAGNOSIS OF VIRAL INFECTIONS, Marcel Dekker, Inc., New York, pp. 329-340 (1985)). Currently, analgesics provide the only treatment for shingles (see R. Boyd, et at., BASIC MEDICAL MICROBIOLOGY, 2nd Edition, Little, Brown and Company, Boston, p. 527, (1981)).
It has been reported that patients with severe herpes simplex (HSV) infections had no antibody titers above that observed in normal patients. This absence of immune response was speculated to be due to a deficiency in the patient's cell mediated immune response (see J. W. St. Geme, et al., New Engl. J. Med. 273, pp. 229-234 (1965)). While there is antibody to HSV-1 in most normal adults, the humoral immune response (antibody production) to the virus appears not to be sufficient to fight off the disease (see C. Ching and C. Lopez, Infect. Immun. 26, pp. 49-56 (1979)). The presence of an immunologically recognized glycoprotein on the cell membrane of herpes infected cells (glycoprotein C) has also been observed. This glycoprotein C is thought to function as a receptor for the third component of immune complement (see M. L. Smiley and H. M. Friedman, J. Vir. 55, pp. 857-861 (1984)).
The absence of a pronounced immune response indicates that other necessary factors are not present or effective in herpes virus infections. In vitro studies have shown that HSV-1 and HSV-2 infected cells can be lysed by the cell-mediated immune NK cells when present in significant numbers (see C. Ching and C. Lopez, Infect. Immun. 26, pp. 49-56 (1979); M. Yasukawa and M. J. Zarling, J. Immunol. 131, pp. 2011-2016 (1983)). Many patients with severe herpes simplex infections have very low NK cell response (see M. Yasukawa and M. J. Zarling, J. Immunol. 131, pp. 2011-2016 (1983)).
Unlike the herpes virus, the influenza virus has been shown experimentally to stimulate NK cells in vitro. It has been suggested that one of the two neuraminidase glycoproteins may be responsible for this stimulation (see J. Arora, et al., J. Virol. 52, pp. 839-845 (1984)). To further define the involvement of NK cell-mediated immune response, the morbidity and mortality effect by influenza viral infections in mice and hamsters in the presence of anti-NK antibodies was investigated (see J. Stein-Stereilen and J. Guffee, J. Immunol. 136, pp. 1435-1441 (1986)). The dramatic increase in morbidity and mortality suggested that both the neuraminidase, as well as NK cells, are necessary for this anti-influenza viral immune response.
This anti-NK induced effect with influenza infection is similar to that observed when HSV infections are severe (see M. Yasukawa and M. J. Zarling, J. Immunol. 131, pp. 2011-2016 (1983)). Another immunomodulator, interferon, was also shown to increase several fold with influenza virus administered intranasally to patients (see F. A. Ennis, et al., Lancet, p. 891-893 (1981)). The proportional relationship between NK cells and interferon has been well established (see G. Trinchieri, et al., J. Exp. Med. 147, pp. 1299-1313 (1978); D. Santoli and H. Koprowski, Immunol Rev. 44 p. 125-163 (1979); T. Timonen, et al, Eur. J. Immunol. 10, pp. 422-427 (1980); O. Hailer, Curr. Top. Microbiol. Immunol. 92, pp. 25-52 (1981); T. Timonen, J. R. Otaldo, and R. B. Herberman, J. Exp. Med. 153, pp. 569-582 (1981); R. M. Welsh, Curr. Top. Microbiol. Immunol. 92, pp. 83-106 (1981); J. Djeu, et al., J. Exp. Med. 156, pp. 1222-1234 (1982)). The influenza virus has neuraminidase glycoproteins as well as hemagglutinin, all of which are thought to play a major role in NK cell-mediated activity (see, D. Arora, et al., J. Virology 52, pp. 839-845 (1984)).
Thus, the apparent persistence of the HSV infection is associated with the absence of the body's immune response to be triggered in herpes infected patients (see J. W. St. Geme, et al., New Engl. J. Med. 273, pp.229-234 (1965); A. J. Nahmias and B. Roizman, New Engl. J. Med. 289, pp. 667-674 (1973); C. Ching and C. Lopez, Infect. Immun. 26, pp. 49-56 (1979); J. Stein-Stereilen and J. Guffee, J. Immunol. 136, pp. 1435-1441 (1986); M. Yasukawa and M. J. Zarling, J. Immunol. 131, pp. 2011-2016 (1983)). The absence of natural killer cell cell-mediated immune response in these patients has been speculated as one possible reason for the persistence of the disease state (see M. Yasukawa and M. J. Zarling, J. Immunol. 131, pp. 2011-2016 (1983); C. Ching and C. Lopez, Infect. Immun. 26, pp. 49-56 (1979); Stein-Stereilen and J. Guffee, J. Immunol. 136, pp. 1435-1441 (1986)).
Disorders Related to Herpes Infection
A number of disorders are thought to be related to herpes virus infection. For example, HIV infection in vitro has been reported to be enhanced in the presence of human herpes virus-6 (HHV-6) (see Gallo, et al., ASM News 56, p. 523 (1990)). Levy, et at., reported that the HHV-6 inhibited infection of peripheral blood mononuclear cells and purified CD4.sup.+ lymphocytes (see Levy, et al., J Clin. Micro. 28, pp. 2362-2364 (1990)).
Nasopharyngeal carcinoma has been associated with Epstein-Barr viral antigens. Patients with nasopharyngeal carcinoma have been shown to exhibit antibodies to soluble Epstein-Barr virus antigens. In addition, antibody titers in patients suffering from nasopharyngeal carcinoma appear when tumor growth is progressive and the same antibodies are frequently not detectable when tumors are regressing (see Piessens, W. F., Cancer, (Phila) 26, p. 1214 (1970)).
Herpes viruses have also been implicated in chronic fatigue syndrome. In particular, the Epstein-Barr virus has been associated with the disease, based in part on several studies describing patients with atypical profiles of antibodies to the Epstein-Barr virus. (For a review, see Lopez, C., (ed.) Immunology and Pathogenesis of Persistent Virus Infections, American Society for Microbiology, Washington, D.C., p. 286 (1988)). Other diseases in which the Herpes virus is implicated are shingles, Herpes Type I (fever blisters), Herpes Type 2 (genital herpes), Burkitt's lymphoma, and mononucleosis (see Davis, et al., MICROBIOLOGY, 4th ed., J. B. Lippincott Company, Philadelphia, p. 929 (1990)).
As summarized hereinabove, infections by herpes-related viruses have been implicated in a wide range of diseases. What is needed is a method of treating disorders that are associated with herpes virus infections so that the immune system of the human or animal can effectively correct the symptoms of the disease state, presumably allowing the immune system to target the diseased tissue. The method and composition should be safe and easy to administer and should be effective in a short period of time after administration with negligible, if any, side effects over a period of time.